CH664959A5 - METHOD FOR PRODUCING SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES. - Google Patents

Description

DESCRIPTION The present invention relates to a process for the preparation of a group of substituted 2,4-diamino-5-benzylpyrimidines.

German patent application No. 2 443 682 discloses, inter alia, compounds of the formula I.

wherein

R4, R5 and R6 as defined above are reacted with formaldehyde 25 and a secondary amine R7R8NH, a compound of the formula V

H-

30th

(I)

k

R HN

ch nr7r8

(V)

35

and their salts, in which

R1 and R: are the same or different and each Q 3-alkyl, C | j-Alkoxy, Ci j-alkenyl or C2 rAlkenyloxy and Z are amino or alkyl-substituted amino.

Antibacterial activity is attributed to these compounds and it was subsequently found that 2,4-diamino-5 (4-amino-3,5-dimethoxy-benzyl) pyrimidine had good diuretic activity.

The German patent application No. 2 634 358 discloses inter alia compounds of the formula II

arises, which then with a compound of formula VI KH.

(VI),

45

reacts, a compound of formula VII

O) "NH2

(VII)

and their salts, in which

R1 is a halogen atom and

Z means amino or alkyl-substituted amino.

Antibacterial activity has also been attributed to these compounds.

A new synthesis of the compounds of the formulas I and II has now been found.

Accordingly, the present invention relates to a process for the preparation of a compound of formula III

arises, followed by reductive removal of the group R9 if R9 is not hydrogen, where 60 R4, R5 and R6 have the meaning described above, R7 and R8 are both Cj 4-alkyl or R7R8NH morpholine or piperidine and R9 is hydrogen, hydroxy, C, 4-alkylthio or mercapto, and then optionally a compound of the formula III, in which 65 R4a is hydrogen, to a compound of the formula III, in which

R4a C | 4-alkyl means N-alkylation.

This process is particularly suitable for production

664 959

4th

those compounds in which R4 is hydrogen. Suitable radicals R "and R6 are the same and each represent methoxy, chlorine or C, 4-alkyl.

The preparation of the compound of formula V of the process is generally carried out under the conditions

tili b die flir die inali * ran MtnniMnai from

Miocque and Vierfond (Bull. Soc. Chem. France, 1970, 1896) are described. The reaction is conveniently carried out in the presence of 0.5 mole of an acid, e.g. Acetic acid, performed per mole of each of the other ingredients. The compound of formula VI is then reacted with a small excess of compound of formula V in the presence of an acid such as p-toluenesulfonic acid. The reaction is normally not carried out at an elevated temperature, suitably between 100 C and 200 C in a solvent with a suitably high boiling point, e.g. in a glycol, such as ethylene glycol. The desulfurization is suitably carried out by hydrogenolysis in the presence of a transition metal catalyst, Raney nickel being particularly suitable for this process. This reaction is usually carried out in a polar solvent, e.g. in a Q 4 alkanol, such as methanol or ethanol.

Any alkylation of the amino group NR4H is carried out under conditions which do not affect the amino groups which are bonded to the pyrimidine ring. Suitable conditions are again known to the person skilled in the art, e.g. the reaction with formic acid and the appropriate aldehyde.

The compounds of the formulas VII are new intermediates and as such form an important part of the present invention.

example 1

Preparation of 2,6-diisopropyl-4-piperidinomethylaniline

According to the conditions described by Miocque and Vierfond (Bull. Soc. Chim. France 1970, 1896), 2,6-diisopropylaniline (17.73 g, 0.10 mol), 37% aqueous formaldehyde (8.1 ml, 0.10 mol), piperidine (8.52 g, 0.10 mol). Acetic acid (3.00 g, 0.05 mol) and ethanol (25 ml) heated together until the temperature of the solution reached 92 ° C. Then the solution was heated under reflux for 24 hours. The product was distilled under vacuum (122 C to 140 C at 0.7 to 0.8 mm) to give the title compound (17.57 g, 64%).

"H NMR (CDClj): 5 1.25 (d, 12, CH3), 1.50 (m, 6, (CH-h). 2.35 (m, 4, N (OL) -,), 2.95 (m, 2, CH), 3.35 (s, 2, Ar-CH :), 3.70 (broad, s, 2, NH2), 7.0 (s, 2, Ar-H).

Example 2

Preparation of 2,6-diethyl-4-pipendinomethylaniline

A solution of 2,6-diethylaniline (29.85 g, 0.20 mol), 37% aqueous formaldehyde (16.2 ml, 0.20 mol), piperidine (17.03 g, 0.20 mol), Acetic acid (6.00 g, 0.10 mol) and ethanol (25 ml) were reacted under conditions similar to Example 1.

The title compound (28.49 g, 57.8%) was isolated by vacuum distillation (115 C to 125 C at 0.05 mm).

'H NMR (CDCU): S 1.25 (t, 6, CH,), 1.50 (m, 6, (CHo) 3), 2.35 (m. 4. N (CH -.) -> j, 2.55 (q, 4, CH, M ~ e), 3.45 (s, 2,

ARCH :). 3.55 (broad s, 2, NH2), 6.90 (s, 2, ArH).

Example 3

Preparation of 2,6-diisopropyl-4- (N, N-dimethylamine amyl umilili

A solution of 2,6-diisopropylaniline (35.45 g, 0.20 mol), 37% aqueous formaldehyde (16.2 ml, 0.20 mol). N.N-dimethylamine (9.02 g, 0.20 mol), acetic acid (6.00 g, 0.10 mol) and ethanol (25 ml) were reacted under conditions similar to Example 1.

The title compound (12.05 g, 26%) was isolated by vacuum distillation (112 C to 120 C, 0.2 mm).

'H NMR (CDCL): 5 1.25 (d, 12, CH-.), 2.20 (s, 6, NMe,),

u? 5 (m.: oi). ] j] (i: Areni), UM 11 mia "

7.0 (see 2nd ArH).

Example 4

Preparation of 2,6-diisopropyl-4-morpholmomethylanilm

A solution of 2,6-diisopropylaniline (35.45 g, 0.20 mol), 37% aqueous formaldehyde (16.2 ml, 0.20 mol), morpholine (17.42 g, 0.20 mol) , Acetic acid (6.00 g, 0.10 mol), and ethanol (25 ml) were reacted under conditions similar to Example 1. After concentrating on a rotary evaporator, the residue was dissolved in diethyl ether and washed with aqueous sodium bicarbonate and water. After the ether solution had dried, a solution of hydrogen chloride (0.20 mol) in ethanol was added. Filtration and drying gave the hydrochloride salt of the title compound (47.58 g, 76.0%). The salt (20.0 g, 0.6 mol) was dissolved in acetone and treated with solid potassium bicarbonate. After filtration and evaporation of the solvent, the title compound was obtained (16.27 g, 92.2%).

C | 7H-.8N->: Calculated: C 73.87; H 10.21; N 10.13 Found: C 74.04; H 10.31; N 10.17.

Example 5

Preparation of 2,4-diamino-5- (4-amino-3,5-diisopropytbenzyl) -6-methylthiopyrimidine

A solution of V (R4 = H, R5 = R5 = CHMe :, NR7R8 = Morpholino) was added to 2,4-diamino-6-methylthiopyrimidine (1.56 g, 10.0 mmol) in ethylene glycol (50 ml) at 114 ° C , 3.32 g, 12.0 mmol) in ethylene glycol (25 ml) and p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) added. The temperature was maintained between 125 ° C and 140 ° C for 3/4 hours, then the solvent was distilled off under vacuum and 3N hydrochloric acid (20 ml) was added to the residue. The crude hydrochloride salt of the title compound (3.44 g, 90.0%) was dissolved in methanol, treated with activated carbon, filtered and evaporated until crystallization started. The slurry was diluted with isopropanol, filtered and dried to give the purified hydrochloride salt of the title compound (2.58 g, 68%).

The title compound was obtained by adding concentrated ammonium hydroxide (6 ml) to an aqueous solution of the hydrochloride salt (1.67 g, 4.37 mmol). Filtration and drying gave the title compound (1.38 g, 91.4%).

'H NMR (CDC1.0: 8 1.30 (d, 12, CH3), 2.60 (s, 3, SCH3), 3.0 (m, 2, CH), 3.6 (broad s, 2, ArNH -.), 3.35 (s, 2, ArCH-), 4.7 (broad s, 4, NH2), 7.0 (s, 2, ArH).

Similarly, VI (R9 = SCH3, 1.56 g, 10.0 mmol) was reacted with V (R4 = H, R5 = R6 = CHMe2, NR7R8 = Pi-peridino, 3.29 g, 12.0 mmol), whereby the title compound was obtained (1.41 g, 41%).

Likewise, under similar conditions VI (R9 = SCH3, 1.56 g, 10.0 mmol) with V (R4 = H, R5 = R6 = CHMe2, R7 = RS = CH3, 2.81 g, 12.0 mmol) reacted, the title compound (0.97 g, 28.4%) being formed.

Example 6

Preparation of 2,4-Diamim> -5- (4-ctmino-3,5-Diisopropylhen-zyl jpyriniidin

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

664 959

A solution of VII (R4 = H, R5 = R6 = CHMe2, R9 = SCH3, 0.50 g, 1.45 mmol) in methyl cellosolve (10 ml) and water (0.5 ml) was treated with Tl Ra for 6 hours -ney nickel (3 g) heated under reflux. The solution was filtered and evaporated and the residue was triturated with hot hexane to give the title compound (0.36 g, 84%), melting point 177 C to 180 C.

Example 7

Preparation of 2,4-diamino-5- (4-amino-3,5-diisopropylben-: yl) -6-hydroxypyrimidine

A solution of VI • H-.0 (R9 = OH, 1.44 g,

10.0 mmol), V (R4 = H, R5 = R6 = CHMe2, NR7R8 = Morpholino, 3.32 g, 12.0 mmol) and p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol ) in ethylene glycol (75 ml) was kept at 133 C to 138 C for 4 1/2 hours. The solvent was distilled off under vacuum and 3N hydrochloric acid (20 ml) was added to the residue. The resulting hydrochloride salt was isolated, dissolved in water and neutralized by adding concentrated ammonium hydroxide to give the title compound (2.36 g, 74.9%). The title compound was purified by recrystallization from ethanol (1.44 g, 45.7%).

'H NMR (DMSO-d6): 8 1.05 (d, 6, CH,), 2.90 (m, 2, CH), 3.30 (s, 2nd ArCH->), 4.15 ( broad s, 2, ArNH,), 5.45 (broad s, 2, NH-0, 4.15 (broad s, 2, NH->), 6.80 (s, 2, ArH), 9.90 (s, 1, OH).

The title linkage can be converted to VII (R9 = 0S02Me) by subsequent reaction with methanesulfonic acid chloride, followed by catalytic hydrogenation with palladium to give compound VII (R9 = H), e.g. in British Patent No. I 542 804.

5 Example 8

Preparation of 2,4-diamino-5- (4-amino-3,5-diisopropylbenzyDpyrimidine

A solution of VI (R9 = H, 1.10 g, 10.0 mmol), V (R4 = H, R5 = R6 = CHMe2, NR7R8 = Morpholino, 3.32 g, 10 12.0 mmol) and p- Toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) in ethylene glycol (50 ml) was heated at 150 ° C. to 160 ° C. for 57 hours. The solvent was distilled off under vacuum and 3N hydrochloric acid (20 ml) was added to the residue. The resulting solution was washed with methylene chloride and evaporated to an oil which crystallized on standing. The crystals were triturated with isopropanol, filtered and dried to give the hydrochloride salt of the title compound (1.51 g, 45%), which was recrystallized from ethanol-20 de (1.04 g, 68.9%).

The addition of 3N sodium hydroxide to the aqueous solution of the hydrochloride salt (0.74 g, 2.20 mmol) gave the title compound (0.50 g, 76%).

'H NMR (DMSO-d6): 5 1.15 (d, 12, CH3), 2.95 (m, 2, 25 CH), 3.50 (s, 2, ArCHO, 4.50 (broad s, 2, ArNH2), 6.15 (broad s, 2, NH2), 6.55 (broad s, 2, NH2), 6.80 (s, 2, ArH), 7.40 (s, 1, pyrimidine 5 -H). Melting point 179 'C to 182 C.

C.

Claims (5)

664 959 2nd PATENT CLAIMS 1. Process for the preparation of a compound of the formula purple ItjN N - ^ Oy> ch2 ~ <^ 0 ^^ ~ NH2 X \ V "4 4a R R 4 4a R R N wherein (inb) (purple) in what R4 is hydrogen or C, 4-alkyl, R4a C, 4-alkyl and io R5 and R6 are the same or different and each represent halogen, Q 4-alkyl or Q 4-alkoxy, characterized in that a compound of formula IV R4 is hydrogen or C | 4-alkyl, R4a hydrogen and R5 and R6 are the same or different and each halogen, 15 C | 4-alkyl or C, 4-alkoxy, characterized in that a compound of formula IV (IV) with formaldehyde and a secondary amine R7R8NH, wherein R7 and R8 each represent Q 4-alkyl or R7R8NH means morpholine or piperidine, to give a compound of the formula V. with formaldehyde and a secondary amine R7R8NH, (IV) wherein R7 and R8 each represent C, 4-alkyl or 25 R7R8NH means morpholine or piperidine, to give a compound of the formula V. R- U r hm ch nr7r8 30th 35 U r hm ch nr7r8 (V) which is then reacted with a compound of the (V) formula VI which is then reacted with a compound of the formula VI (VI), 45 wherein (VI), R9 is hydrogen, hydroxy, Ci ^ alkylthio or mercapto, to a compound of formula VII 50 wherein R9 is hydrogen, hydroxy, C, 4-alkylthio or mercapto r hn, to a compound of formula VII • 5. oVck2 / o y ™ - 55 (VII) HxN implemented, the group R9 then reductively removed if it is not hydrogen and the resulting compound (VII) 60 of the formula IIIb, in which R4a is hydrogen, is N-Ci-C4-alkylated. 3. The method according to claim 1, characterized in that one implements the reaction of a compound of formula V, and then removes the group R9 reductively, 65 with a compound of formula VI in the presence of one if it is not hydrogen. Acid performs. 2. Process for the preparation of a compound of the 4. Process according to claim 3, characterized in that with the fact that p-toluenesulfonic acid is used as the acid. 3rd 664 959 5. The method according to claim 1, characterized in that R9 is hydrogen, hydroxy or C | -C4-alkylthio. 6. Compounds of formula VII (VII) wherein R4 is hydrogen or Q4-alkyl, R5 and R6 are the same or different and each halogen, C | 4-alkyl or C, 4-alkoxy and R9 is hydroxy, C, 4-alkylthio or mercapto and their acid addition salts as intermediates in the process according to claim 1 or 2. 4 4a R R N wherein (HD. R4 and R4a are the same or different and each have a hydrogen atom or a Ci 4-alkyl group, RÄ is halogen, C, 4-alkyl or Q 4-alkoxy and R6 is halogen, Q 4-alkyl or Ci 4-alkoxy; which is characterized in that a compound of formula IV 15 r4hn 20th (IV)